The main focus of this research proposal is to further explore the effect of the Chrna4 A529T polymorphism on nAChR function and behavioral sensitivity to nicotine using a mouse model that has been engineered to differ at the Chma4 A529T polymorphism. These studies will increase our understanding of the effect of this single amino acid change on nAChR function. By understanding how this polymorphism affects individual differences in the reinforcing and aversive effects of nicotine between adolescent and adult animals, we might gain new information of how naturally occurring genetic variability influences innate nicotine sensitivity and whether genetic influence in adolescents is stronger or weaker compared to adult animals. The proposal will specific try to establish which nicotine addiction-related behaviors are influenced by the Chrna4 A529T polymorphism in both adolescents and adults. Chrna4 knocking mice will be used to examine the effect of the polymorphism on nicotine oral preference, conditioned place preference, tolerance development, and conditioned taste aversion. Behavioral measures will provide new information regarding the reinforcing properties of nicotine measured in preference, development of tolerance, and aversion, which are behaviors that influence nicotine addition. Additionally, including adolescent animals will provide information regarding how age might influence some of these behaviors. The proposal will also determine the influence of the Chrna4 A529T polymorphism on the function and expression of a4(32* nAChRs in both adolescents and adults. Specifically, Chrna4 T529A knockin mice will be used to evaluate the genetic effect of the polymorphism on Rb+ efflux, gamma-aminobutyric acid (GABA) release, dopamine (DA) release, [3H] cytisine binding in specific brain regions. Gathering data on these measures on both adolescent and adult mice will allow for a comparison of the function and expression of a4(32* nAChRs in order to further evaluate how age might influence biochemical and functional measures. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: More than 438,000 people die each year due to smoking, making smocking the most preventable cause of death in the United States, and more than 70% of smokers want to qui' smoking; however very few (2.5%) are successful each year. Research has provided substantial evidence that nicotine addiction has a genetic component and more recent evidence, due to the fact that 80% smokers initiate use before the age of 18, that there is also a large age related component. This proposal will use a genetic approach in order to determine the influence of age on behavior and biochemica measures related to nicotine addiction. [unreadable] [unreadable] [unreadable]